Linezolid

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LINEZOLID

Composition:

Active substance: linezolid;

1 tablet contains linezolid 600 mg;

Excipients: maize starch, microcrystalline cellulose, hydroxypropylcellulose, sodium starch glycolate, magnesium stearate, coating (hypromellose, titanium dioxide (E 171), macrogol, propylene glycol).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: oval-shaped tablets, convex on both upper and lower surfaces, coated with a film coating of white or almost white color.

Pharmacotherapeutic group. Antibacterial agents for systemic use.
ATC code J01X X08.

Pharmacological Properties

Pharmacodynamics

Linezolid is a synthetic antibacterial agent belonging to a new class of antimicrobial agents — oxazolidinones. It exhibits in vitro activity against aerobic Gram-positive bacteria and anaerobic microorganisms. Linezolid selectively inhibits bacterial protein synthesis through a unique mechanism of action. It directly binds to bacterial ribosomes (23S subunit of 50S) and interferes with the formation of the functional 70S initiation complex (an essential component of the translation process).

The prevalence of acquired resistance in individual species may vary geographically and over time; therefore, it is advisable to refer to local data on microbial resistance, especially when treating severe infections. If necessary, when the local prevalence of microbial resistance is such that the benefit of using the medicinal product, at least for certain types of infections, is questionable, expert consultation should be sought.

Susceptible microorganisms

Gram-positive aerobic microorganisms: Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, coagulase-negative staphylococci, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, group C streptococci, group G streptococci.

Gram-positive anaerobic microorganisms: Clostridium perfringens, Peptostreptococcus anaerobius, species of Peptostreptococcus.

Resistant microorganisms: Haemophilus influenzae, Moraxella catarrhalis, species of Neisseria, Enterobacteriaceae, species of Pseudomonas.

* Clinical efficacy has been demonstrated for susceptible strains according to approved indications.

Although linezolid demonstrates some in vitro activity against Legionella, Chlamydia pneumoniae, and Mycoplasma pneumoniae, there is insufficient data to confirm clinical efficacy in these cases.

Cross-resistance

The mechanism of action of linezolid differs from that of other classes of antibiotics. In vitro studies of clinical strains (methicillin-resistant staphylococci, vancomycin-resistant enterococci, as well as penicillin- and erythromycin-resistant streptococci) show that linezolid is generally active against microorganisms resistant to one or more other classes of antimicrobial agents.

Resistance to linezolid is associated with point mutations in the 23S rRNA.

Pharmacokinetics

The medicinal product Linezolid contains linezolid, which is the biologically active substance and is metabolized to inactive derivatives.

Absorption

Linezolid is extensively absorbed after oral administration. Maximum plasma concentration is reached approximately 1–2 hours after dosing, and absolute bioavailability is about 100%. Therefore, linezolid can be administered orally or intravenously without dose adjustment.

Linezolid can be administered regardless of food intake. Time to maximum concentration increases from 1.5 to 2.2 hours, and Cmax decreases by approximately 17% when linezolid is taken with a high-fat meal. However, total exposure, assessed as AUC0–∞, is similar in both cases.

Distribution

Pharmacokinetic studies have shown that linezolid rapidly distributes into well-perfused tissues. Approximately 31% of linezolid is protein-bound in plasma, and this binding is independent of drug concentration. The volume of distribution at steady state in healthy adult volunteers averages 40–50 L.

After multiple dosing, linezolid concentrations were measured in various fluids in a limited number of phase 1 study volunteers. The ratio of linezolid concentration in saliva to plasma concentration was 1.2:1, and the ratio of linezolid concentration in sweat to plasma concentration was 0.55:1.

Metabolism

Linezolid is primarily metabolized via oxidation of the morpholine ring, forming two inactive ring-opened carboxylic acid metabolites: the aminoethoxyacetic acid metabolite (A) and the hydroxyethylglycine metabolite (B). Formation of metabolite A is believed to be enzyme-mediated, whereas formation of metabolite B is mediated by a non-enzymatic mechanism involving chemical oxidation under in vitro conditions. In vitro studies have demonstrated that linezolid is minimally metabolized, with possible involvement of the human cytochrome P450 system. However, the metabolic pathways of linezolid are not fully understood.

Excretion

Non-renal clearance accounts for approximately 65% of total linezolid clearance. At steady state, about 30% of the dose is recovered in urine as linezolid, 40% as metabolite B, and 10% as metabolite A. Mean renal clearance of linezolid is 40 mL/min, indicating tubular reabsorption. Linezolid is virtually undetectable in feces, whereas approximately 6% of the dose is recovered in feces as metabolite B and 3% as metabolite A.

Minor non-linearity in clearance was observed with increasing linezolid doses, apparently due to lower renal and non-renal clearance at higher concentrations. However, this difference in clearance was minor and did not affect the apparent elimination half-life.

Patients with renal impairment. Pharmacokinetics of linezolid are not altered in patients with any degree of renal impairment; however, the two main metabolites of linezolid accumulate in patients with renal impairment, with increasing accumulation in patients with more severe renal dysfunction. The pharmacokinetics of linezolid and its two metabolites were also studied in patients with end-stage renal disease (ESRD) undergoing hemodialysis. In this study, 14 patients received 600 mg of linezolid every 12 hours for 14.5 days. Since similar plasma concentrations of linezolid were achieved regardless of renal function, dose adjustment is not required for patients with renal impairment. However, considering the lack of information on the clinical significance of accumulation of the main metabolites, the appropriateness of using linezolid in patients with renal impairment and the potential risks of metabolite accumulation should be carefully considered. Both linezolid and its two metabolites are removed by hemodialysis. There is no information on the effect of peritoneal dialysis on the pharmacokinetics of linezolid.

Patients with hepatic impairment. Pharmacokinetics of linezolid were not altered in 7 patients with mild to moderate hepatic dysfunction (Child-Pugh class A or B). Based on available data, dose adjustment is not recommended for patients with mild to moderate hepatic impairment. Pharmacokinetics in patients with severe hepatic impairment have not been evaluated.

Children and adolescents (under 18 years of age). Data on the safety and efficacy of linezolid in children and adolescents (under 18 years of age) are insufficient to recommend its use in this age group (see section "Dosage and administration").

Further studies are needed to determine safe and effective dosing regimens. Pharmacokinetic studies indicate that clearance of linezolid (normalized per kilogram of body weight) after single and multiple doses was higher in children (aged 1 week to 12 years) than in adults, but decreased with age.

In children aged 1 week to 12 years, administration of linezolid at a dose of 10 mg/kg every 8 hours daily provides exposure approaching that achieved in adults receiving 600 mg twice daily.

In neonates, systemic clearance of linezolid (normalized per kilogram of body weight) increases rapidly during the first week of life. Therefore, when linezolid is administered at a dose of 10 mg/kg every 8 hours daily, systemic exposure will be highest on the first day of life. However, excessive accumulation of the drug is not expected during the first week of life with this dosing regimen, as drug clearance increases rapidly during this period.

In adolescents (aged 12 to 17 years), the pharmacokinetics of linezolid are similar to those in adults when the drug is administered at a dose of 600 mg. Thus, adolescents receiving 600 mg every 12 hours daily will have the same exposure as adults receiving the same dose.

After single or multiple doses of linezolid in children with ventriculoperitoneal shunts receiving 10 mg/kg linezolid every 12 or every 8 hours, variable concentrations of linezolid were observed in cerebrospinal fluid. Therapeutic concentrations in cerebrospinal fluid were not achieved or consistently maintained. Therefore, the use of linezolid for empirical treatment of children with central nervous system infections is not recommended.

Elderly patients. Pharmacokinetics of linezolid are not significantly altered in individuals aged 65 years and older.

Women. Women have a lower volume of distribution compared to men, and mean clearance (adjusted for body weight) is approximately 20% lower. Plasma concentrations of linezolid are higher in women, which may be partly explained by differences in body weight. However, since the mean elimination half-life in men and women does not differ significantly, plasma concentrations in women are not expected to substantially exceed well-tolerated levels; therefore, dose adjustment is not required.

Clinical Characteristics

Indications

Hospital-acquired pneumonia.

Community-acquired pneumonia.

Linezolid is indicated in adults for the treatment of community-acquired pneumonia and hospital-acquired pneumonia when it is known or suspected to be caused by susceptible Gram-positive bacteria. When determining the appropriateness of linezolid therapy, results of microbiological investigations or information on the prevalence of antimicrobial resistance among Gram-positive bacteria should be taken into account (see section "Pharmacological Properties. Pharmacodynamics").

Linezolid is not active against infections caused by Gram-negative pathogens. Therefore, if such an infection is confirmed or suspected, specific therapy against Gram-negative microorganisms should be initiated concomitantly.

Complicated skin and soft tissue infections (see section "Special Warnings and Precautions for Use").

Linezolid is indicated in adults for the treatment of complicated skin and soft tissue infections only when microbiological testing has confirmed that the infection is caused by susceptible Gram-positive bacteria.

Linezolid is not active against infections caused by Gram-negative pathogens. The medicinal product should be used in patients with complicated skin and soft tissue infections with confirmed or suspected concomitant Gram-negative infection only when there are no alternative treatment options (see section "Special Warnings and Precautions for Use"). In such cases, concomitant treatment for the Gram-negative infection should be initiated.

Initiation of linezolid therapy should occur only in a hospital setting and after consultation with an appropriate specialist, such as a microbiologist or infectious disease specialist.

Official recommendations on the appropriate use of antibacterial agents should be taken into account.

Contraindications

Hypersensitivity to linezolid or to any of the excipients.

Linezolid must not be used in patients receiving any medicinal products that inhibit monoamine oxidase A and B (e.g., phenelzine, isocarboxazid, selegiline, moclobemide), or within two weeks of discontinuation of such agents.

Except in cases where careful observation and monitoring of blood pressure are possible, linezolid must not be administered to patients in the following circumstances:

• uncontrolled hypertension, pheochromocytoma, carcinoid, thyrotoxicosis, bipolar depression, schizoaffective disorder, acute episodes of vertigo;
• concomitant use of serotonin reuptake inhibitors, tricyclic antidepressants, 5-HT₁ serotonin receptor agonists (triptans), direct and indirect sympathomimetics (including adrenergic bronchodilators, pseudoephedrine, phenylpropanolamine), vasopressors (epinephrine, norepinephrine), dopaminergic compounds (dopamine, dobutamine), meperidine, or buspirone.

Breastfeeding must be discontinued during treatment (see section "Use in Pregnancy and Lactation").

Interaction with Other Medicinal Products and Other Forms of Interaction

Monoamine oxidase inhibitors

Linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAO). In drug interaction and safety studies, very limited data have been obtained on the use of linezolid in patients receiving concomitant therapy with agents that pose certain risks due to MAO inhibition. Therefore, the use of linezolid under such circumstances is not recommended unless close monitoring of the patient is possible (see sections "Contraindications", "Special Warnings and Precautions for Use").

Potential interactions leading to increased blood pressure

In healthy volunteers with normal blood pressure, linezolid potentiates the blood pressure increase caused by pseudoephedrine and phenylpropanolamine hydrochloride. Concomitant administration of linezolid with pseudoephedrine or phenylpropanolamine hydrochloride results in an average increase in systolic blood pressure of 30–40 mm Hg, compared with an increase of 11–15 mm Hg with linezolid alone, 14–18 mm Hg with pseudoephedrine or phenylpropanolamine alone, and 8–11 mm Hg with placebo. Similar studies have not been conducted in patients with hypertension. Careful dose titration of agents with vasopressor effects, particularly dopaminergic agents, is recommended to achieve the desired outcome when used concomitantly with linezolid.

Potential serotonergic interactions

Potential interactions between linezolid and dextromethorphan were studied in a trial involving healthy volunteers. Participants received dextromethorphan (two 20 mg doses administered 4 hours apart) with or without linezolid. In healthy volunteers receiving linezolid and dextromethorphan, no symptoms of serotonin syndrome (confusion, hallucinations, agitation, tremor, pathological flushing, diaphoresis, hyperpyrexia) were observed.

Post-marketing experience: one report of symptoms resembling serotonin syndrome was received in a patient receiving linezolid and dextromethorphan; these symptoms resolved after discontinuation of both drugs.

During clinical use of linezolid with serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and opioids, cases of serotonin syndrome have been reported. Thus, although the concomitant use of these agents is contraindicated (see section "Contraindications"), management of patients for whom treatment with both linezolid and serotonergic agents is essential is described in section "Special Warnings and Precautions for Use".

Concomitant use with tyramine-rich foods

In patients receiving linezolid and tyramine in amounts less than 100 mg, no significant pressor effect was observed. This indicates that only excessive consumption of foods and beverages high in tyramine (namely: aged cheeses, yeast extracts, non-distilled alcoholic beverages, and fermented soy products such as soy sauce) should be avoided.

Medicinal products metabolized by cytochrome P450

Linezolid is not metabolized by the cytochrome P450 enzyme system and does not inhibit the function of any of the clinically significant human cytochrome P450 isoenzymes (1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Similarly, linezolid does not induce cytochrome P450 isoenzymes in rats. Therefore, an effect of linezolid on the pharmacokinetics of other medicinal products metabolized by CYP450 is not expected.

Rifampicin. The effect of rifampicin on the pharmacokinetics of linezolid was studied in 16 healthy male volunteers who received linezolid (600 mg twice daily for 2.5 days) with and without rifampicin (600 mg once daily for 8 days). Rifampicin reduced C_max and AUC of linezolid by 21% (90% CI: 15–27) and 32% (90% CI: 27–37), respectively. The mechanism of this interaction and its clinical significance are unknown.

Warfarin. A 10% reduction in mean maximum INR (International Normalized Ratio) was observed at steady state when warfarin was added to linezolid treatment, with a 5% reduction in INR AUC. However, available data are insufficient to assess the clinical significance of this interaction.

Special precautions for use

Myelosuppression

Cases of myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) have been reported in patients receiving linezolid. In cases where the outcome was known, hematological parameters returned to pre-treatment levels after discontinuation of linezolid. The risk of developing these effects appears to be related to the duration of treatment. Elderly patients receiving linezolid have an increased risk of developing blood dyscrasias compared to younger patients. Thrombocytopenia occurs more frequently in patients with severe renal insufficiency, regardless of whether they are on dialysis or not, and in patients with moderate to severe hepatic insufficiency. Therefore, careful monitoring of blood counts is recommended in patients: with pre-existing anemia, granulocytopenia, or thrombocytopenia; receiving concomitant medicinal products that may reduce hemoglobin levels, suppress hematopoiesis, or negatively affect platelet count or function; with acute renal failure or moderate to severe hepatic impairment; or receiving treatment for more than 10–14 days. Linezolid should be administered to such patients only with careful monitoring of hemoglobin levels, complete blood count parameters, and platelet counts.

If significant myelosuppression develops during treatment with linezolid, therapy should be discontinued, except when continuation is considered absolutely necessary; in such cases, intensive monitoring of complete blood count parameters and appropriate therapeutic interventions should be implemented.

Furthermore, weekly monitoring of complete blood count parameters (including hemoglobin levels, platelet count, total and differential white blood cell count) is recommended in all patients receiving linezolid, regardless of initial blood test results.

In studies using an unapproved medicinal product under a compassionate use program, an increased incidence of severe anemia was observed in the group of patients who received linezolid for more than 28 days (the maximum recommended duration of treatment). These patients more frequently required blood transfusions. Cases of anemia requiring blood transfusion have also been reported in the post-marketing period. Such anemia occurred more frequently in patients who received linezolid for longer than 28 days.

In the post-marketing period, cases of sideroblastic anemia have been reported. In cases where the onset of disease was known, most patients had received linezolid for more than 28 days. Most patients recovered fully or partially after discontinuation of linezolid, with or without treatment for anemia.

Imbalance in mortality in a clinical trial in patients with catheter-related infections

In an open-label study involving critically ill patients with catheter-related bloodstream infections, an increased mortality rate was observed in patients receiving linezolid compared to the vancomycin/dicloxacillin/oxacillin treatment groups [78/363 (21.5%) vs. 58/363 (16.0%)].

The primary factor influencing mortality was the Gram-positive infection status at baseline.

Mortality rates were similar in patients with infections caused exclusively by Gram-positive microorganisms (odds ratio 0.96; 95% CI: 0.58–1.59), but were significantly higher (p = 0.0162) in the linezolid group among patients with any other pathogen or no pathogen at baseline (odds ratio 2.48; 95% CI: 1.38–4.46). The greatest imbalance occurred during treatment and within 7 days after discontinuation of the investigational medicinal product. Most patients who received linezolid became infected with Gram-negative pathogens during the study and died from infections caused by Gram-negative organisms or polymicrobial infections. Therefore, in complicated skin and soft tissue infections in patients with confirmed or suspected concomitant Gram-negative infection, linezolid should be used only when no alternative treatment options are available (see section "Indications"). In such cases, concomitant therapy for Gram-negative infection should be initiated.

Antibiotic-associated diarrhea and colitis

Antibiotic-associated diarrhea and antibiotic-associated colitis, including pseudomembranous colitis and Clostridium difficile-associated diarrhea, have been reported with the use of nearly all antibiotics, including linezolid. The severity of manifestations may range from mild diarrhea to fatal colitis. It is therefore important to consider this diagnosis in patients who develop severe diarrhea during or after treatment with linezolid. If antibiotic-associated diarrhea or antibiotic-associated colitis is suspected or confirmed, current antibacterial therapy, including linezolid, should be discontinued and appropriate therapeutic measures should be initiated immediately. Medicinal products that inhibit peristalsis are contraindicated in this situation.

Lactic acidosis

Cases of lactic acidosis have been reported during treatment with linezolid. Patients who develop signs and symptoms of metabolic acidosis during linezolid therapy, including intermittent nausea or vomiting, abdominal pain, low bicarbonate levels, or hyperventilation, should seek immediate medical attention. If lactic acidosis occurs, the benefits of continuing linezolid therapy should be weighed against potential risks.

Mitochondrial dysfunction

Linezolid inhibits mitochondrial protein synthesis. As a result of this inhibition, adverse effects such as lactic acidosis, anemia, and neuropathy (optic and peripheral) may occur; these events are more frequently observed when the drug is used for longer than 28 days.

Serotonin syndrome

Spontaneous reports of serotonin syndrome associated with concomitant use of linezolid and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and opioids, have been received (see section "Interaction with other medicinal products and other forms of interaction"). Therefore, concomitant use of linezolid and serotonergic agents is contraindicated (see section "Contraindications"), except when treatment with linezolid and concomitant serotonergic agents is necessary. In such cases, the patient should be under close surveillance for signs and symptoms of serotonin syndrome, such as cognitive dysfunction, hyperpyrexia, hyperreflexia, and motor incoordination.

If these symptoms occur, the physician should consider discontinuing one or both agents; symptoms of withdrawal may occur after discontinuation of the serotonergic agent.

Rhabdomyolysis

Cases of rhabdomyolysis have been reported with the use of linezolid. Linezolid should be used with caution in patients with risk factors for rhabdomyolysis. If signs or symptoms of rhabdomyolysis occur, linezolid should be discontinued and appropriate therapy initiated.

Hyponatremia and syndrome of inappropriate antidiuretic hormone secretion

Hyponatremia and/or syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been observed in some patients taking linezolid. Regular monitoring of serum sodium levels is recommended in patients at risk of hyponatremia, particularly elderly patients or other patients taking medicinal products that may reduce serum sodium levels (e.g., thiazide diuretics such as hydrochlorothiazide).

Peripheral neuropathy and optic nerve neuropathy

Cases of peripheral neuropathy, as well as optic neuropathy and optic neuritis, sometimes progressing to vision loss, have been reported in patients receiving linezolid therapy. These reports primarily involved patients whose treatment lasted longer than 28 days (the maximum recommended duration of treatment).

All patients should inform their physician if symptoms of visual disturbances occur, such as changes in visual acuity, changes in color vision, blurred vision, or loss of part of the visual field. In such cases, prompt ophthalmologic evaluation is recommended when necessary. Patients receiving linezolid for longer than the recommended 28 days should have regular vision examinations.

If peripheral neuropathy or optic neuropathy develops, the benefits of continuing linezolid therapy should be weighed against potential risks.

The risk of developing neuropathies may be increased when linezolid is used in patients who are undergoing or have recently undergone treatment with antibacterial agents for tuberculosis.

Seizures

Cases of seizures have been reported in patients receiving linezolid therapy. In most cases, patients had a risk factor such as a history of seizures. Patients should inform their physicians if they have previously experienced seizures.

Monoamine oxidase inhibitors

Linezolid is a reversible, non-selective inhibitor of monoamine oxidase (MAO); however, at doses used for antibacterial therapy, it does not exhibit antidepressant effects. There are very limited data on drug interaction studies regarding the safety of linezolid when used in patients with concomitant diseases and/or concomitant medications that may pose a risk due to MAO inhibition. Therefore, the use of linezolid under such circumstances is not recommended unless close observation and monitoring of the patient can be ensured (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use with tyramine-rich foods

Patients should be advised to avoid consuming large amounts of foods rich in tyramine (see section "Interaction with other medicinal products and other forms of interaction").

Superinfection

The impact of linezolid therapy on normal flora has not been evaluated in clinical trials.

Antibiotic use may occasionally lead to overgrowth of non-susceptible organisms. For example, approximately 3% of patients receiving recommended doses of linezolid developed drug-related candidiasis during clinical trials. Appropriate measures should be taken if superinfection occurs during therapy.

Special patient groups

Linezolid should be used with particular caution in patients with severe renal impairment and only when the expected benefit outweighs the potential risk (see sections "Dosage and administration" and "Pharmacological properties. Pharmacokinetics").

Linezolid should be prescribed to patients with severe hepatic impairment only when the expected benefit outweighs the potential risk (see sections "Dosage and administration" and "Pharmacological properties. Pharmacokinetics").

Impairment of fertility

Linezolid reversibly reduced fertility and caused morphological abnormalities in spermatozoa in adult male rats at exposure levels approximately equivalent to those expected in humans; the potential effect of linezolid on male reproductive function is unknown (see section "Pharmacological properties. Pharmacodynamics").

Clinical trials

The safety and efficacy of linezolid when used for longer than 28 days have not been established.

Controlled clinical trials did not include patients with diabetic foot infections, pressure ulcers, ischemic wounds, severe burns, or gangrene. Therefore, experience with the use of linezolid for the treatment of these conditions is limited.

Sodium content

The medicinal product Linezolid, film-coated tablets, contains less than 1 mmol of sodium (23 mg) per tablet. Patients on a low-sodium diet should be informed that this medicinal product is practically sodium-free.

Use during pregnancy or breastfeeding

Use during pregnancy. Data on the use of linezolid in pregnant women are limited. Animal studies have demonstrated reproductive toxicity. There is a potential risk for humans. Linezolid should not be used during pregnancy except when the expected benefit outweighs the potential risk.

Use during breastfeeding. Animal studies have shown that linezolid and its metabolites can pass into breast milk. Therefore, women should discontinue breastfeeding during treatment with this medicinal product.

Fertility. In animal studies, linezolid caused reduced fertility.

Ability to affect reaction speed when driving or operating machinery. Patients should be warned about the possibility of developing dizziness or visual disturbances (see sections "Special precautions for use" and "Undesirable effects") during treatment with linezolid and advised not to drive or operate machinery if these symptoms occur.

Method of Administration and Dosage

Linezolid can be initiated as therapy in the form of an infusion solution, film-coated tablets, or oral suspension.

Patients who begin treatment with the parenteral formulation may be switched to the oral formulation when clinically indicated. In such cases, dosage adjustment is not required, as the bioavailability of linezolid following oral administration is approximately 100%.

Recommended dosage and duration of treatment for adults

The duration of treatment depends on the causative pathogen, site and severity of infection, as well as the clinical response to therapy.

The recommendations for treatment duration provided below are based on results from clinical studies. Shorter treatment regimens may be appropriate for certain types of infections, but have not been evaluated in clinical trials.

The maximum duration of treatment is 28 days. The safety and efficacy of linezolid administered for more than 28 days have not been established (see section "Special precautions for use").

There is no need to increase the recommended dose or duration of treatment for infections associated with bacteremia.

Dosage recommendations for linezolid in the form of infusion solution and tablets/granules for oral suspension are identical and are provided below:

Elderly people

Dose adjustment is not required.

Renal function impairment

Dose adjustment is not required (see sections "Special precautions" and "Pharmacological properties. Pharmacokinetics").

Severe renal impairment (i.e. CLCr < 30 mL/min)

Dose adjustment is not required. Due to the lack of data on the clinical significance of increased exposure (up to 10-fold) to two major metabolites of linezolid in patients with severe renal impairment, the drug should be used with particular caution in such patients and only when the expected benefit outweighs the potential risk.

Since approximately 30% of the linezolid dose is removed during 3 hours of hemodialysis, the drug should be administered to patients undergoing hemodialysis after the dialysis session. The major metabolites of linezolid are partially removed by hemodialysis, but their concentrations after the procedure remain significantly higher than in patients with normal renal function or mild to moderate renal impairment.

Therefore, linezolid should be used with particular caution in patients with severe renal impairment undergoing dialysis, and only when the expected benefit outweighs the potential risk.

Currently, there is no experience with the use of linezolid in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) or receiving renal replacement therapy by alternative methods (other than hemodialysis).

Hepatic impairment

Dose adjustment is not required. However, due to limited clinical data, linezolid should be used in such patients only when the expected benefit outweighs the potential risk (see sections "Special precautions" and "Pharmacological properties").

Route of administration

The recommended dose of linezolid should be administered orally twice daily.

Film-coated tablets may be taken regardless of food intake.

Children

The safety and efficacy of linezolid in children (under 18 years of age) have not been established. Available data to date are presented in the sections "Adverse reactions" and "Pharmacological properties", but no dosage recommendations can be provided.

Overdose

No specific antidote is known.

No cases of overdose have been reported.

In case of overdose, symptomatic treatment together with measures to support glomerular filtration should be administered. Approximately 30% of the administered dose of the drug is removed during 3 hours of hemodialysis, but there are no data on the elimination of linezolid during peritoneal dialysis or hemoperfusion procedures. The two major metabolites of linezolid are also removed by hemodialysis.

Adverse Reactions

The data on adverse reactions listed below were obtained from clinical studies in which more than 6000 adult patients received the recommended doses of linezolid for up to 28 days.

The most frequently reported adverse reactions were diarrhea (8.9%), nausea (6.9%), vomiting (4.3%), and headache (4.2%).

The most common adverse reactions leading to discontinuation of the drug were: headache, diarrhea, nausea, and vomiting. Approximately 3% of patients discontinued treatment due to drug-related adverse reactions.

In addition to the listed reactions, adverse reactions reported during the post-marketing period have been included. Since the frequency of occurrence of these reactions cannot be determined from the available data, they are listed as "frequency unknown".

For the purpose of determining the frequency of adverse reactions, the following classification is used: very common (≥ 1/10), common (> 1/100, < 1/10), uncommon (> 1/1000, < 1/100), rare (> 1/10000, < 1/1000), very rare (< 1/10000), and frequency not known (cannot be estimated based on available data).

* See section "Special warnings and precautions for use".

** See sections "Contraindications" and "Interaction with other medicinal products and other forms of interactions".

† In controlled clinical trials where linezolid was administered for up to 28 days, anemia was observed in 2.0% of patients. During use of the unapproved medicinal product under a compassionate use program in patients with life-threatening infections and concomitant diseases, the proportion of patients who developed anemia after receiving linezolid for ≤ 28 days was 2.5% (33 out of 1326), compared to 12.3% (53 out of 430) in those treated for > 28 days. The proportion of documented cases of severe anemia requiring blood transfusion attributed to the medicinal product was 9% (3 out of 33) in patients treated for ≤ 28 days and 15% (8 out of 53) in those treated for > 28 days.

In rare cases, adverse reactions associated with linezolid administration were severe: localized abdominal pain, transient ischemic attack, and arterial hypertension.

Children

Safety data from clinical trials involving more than 500 pediatric patients (from birth to 17 years of age) do not indicate differences in the safety profile of linezolid in children compared to adult patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 2.5 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging. 10 tablets in a blister, 1 blister per cardboard box.

Prescription status. Prescription only.

Manufacturer. JSC "Lubnifarm".

Manufacturer's address and place of business. 16 Barvinkova Street, Lubny, Poltava Oblast, 37500, Ukraine.